Racial and Ethnic Differences in Graft Loss Among Female Liver Transplant Recipients.

BACKGROUND: Racial differences in post-liver transplantation (LT) outcomes are identified in predominantly male cohorts. Despite known sex differences in a spectrum of liver-related outcomes, it is not known how race influences graft outcomes in women. METHODS: Using the Scientific Registry of Transplant Recipients, we examined race and ethnicity and graft loss (death or retransplant) in women transplanted from 2002 to 2012. Covariates included recipient and donor characteristics, socioeconomics, and medical comorbidities. RESULTS: The eligible cohort (n = 15,860) included 11,051 Caucasians, 2171 Hispanics, 1876 African Americans (AAs), and 762 Asian women with median follow-up of 3.1 years. Five-year graft survival was lower in AA women (60%) compared with Caucasians (71%), Hispanics (70%), and Asians (73%) (P < .001). Graft loss was 45% higher among AA women <40 years at transplant compared with AA women aged 50 to 59 (hazard ratio 1.45, 95% confidence interval 1.17-1.81) and aged 60 to 69 years (hazard ratio 1.33, 95% confidence interval 1.03-1.71), and risk increased after age 60 among Caucasians (P < .001 for race-age interactions). Increased graft loss among young AA women was limited to the first 2 years post-LT (P = .002). CONCLUSION: Younger AA women are at particularly high risk for graft loss, which predominates in the first 2 years post-LT. Prospective studies of immunosuppression adherence and pharmacokinetics, particularly in relation to patient age, may help to explain the mechanisms underlying the higher rates of graft loss in younger AA women.

Clinical and metabolic effects associated with weight changes and obeticholic acid in non-alcoholic steatohepatitis.

BACKGROUND: In a 72-week, randomised controlled trial of obeticholic acid (OCA) in non-alcoholic steatohepatitis (NASH), OCA was superior to placebo in improving serum ALT levels and liver histology. OCA therapy also reduced weight. AIMS: Because weight loss by itself can improve histology, to perform a post hoc analysis of the effects of weight loss and OCA treatment in improving clinical and metabolic features of NASH. METHODS: The analysis was limited to the 200 patients with baseline and end-of-treatment liver biopsies. Weight loss was defined as a relative decline from baseline of 2% or more at treatment end. RESULTS: Weight loss occurred in 44% (45/102) of OCA and 32% (31/98) of placebo-treated patients (P = 0.08). The NAFLD Activity score (NAS) improved more in those with than without weight loss in both the OCA- (-2.4 vs -1.2, P<0.001) and placebo-treated patients (-1.2 vs -0.5, P = 0.03). ALT levels also improved in those with vs without weight loss in OCA- (-43 vs -34 U/L, P = 0.12) and placebo-treated patients (-29 vs -10 U/L, P = 0.02). However, among those who lost weight, OCA was associated with opposite effects from placebo on changes in alkaline phosphatase (+21 vs -12 U/L, P<0.001), total (+13 vs -14 mg/dL, P = 0.02) and LDL cholesterol (+18 vs -12 mg/dL, P = 0.01), and HbA1c (+0.1 vs -0.4%, P = 0.01). CONCLUSIONS: OCA leads to weight loss in up to 44% of patients with NASH, and OCA therapy and weight loss have additive benefits on serum aminotransferases and histology. However, favourable effects of weight loss on alkaline phosphatase, lipids and blood glucose seen in placebo-treated patients were absent or reversed on OCA treatment. These findings stress the importance of assessing concomitant metabolic effects of new therapies of NASH. Clinical trial number: NCT01265498.

Ledipasvir-sofosbuvir and sofosbuvir plus ribavirin in patients with chronic hepatitis C and bleeding disorders.

INTRODUCTION: Chronic hepatitis C virus (HCV) infection is prevalent among patients with inherited bleeding disorders and is a leading cause of mortality in those with haemophilia. AIM: We evaluated the efficacy and safety of ledipasvir-sofosbuvir and sofosbuvir plus ribavirin in patients with chronic HCV genotype 1-4 infection and an inherited bleeding disorder. METHODS: Ledipasvir-sofosbuvir was administered for 12 weeks to patients with genotype 1 or 4 infection and for 12 or 24 weeks to treatment-experienced cirrhotic patients with genotype 1 infection. Patients with genotype 2 and 3 infection received sofosbuvir plus ribavirin for 12 and 24 weeks respectively. RESULTS: The majority of the 120 treated patients had a severe bleeding disorder (55%); overall, 65% of patients had haemophilia A and 26% of patients had haemophilia B; 22% were HIV coinfected. Sustained virologic response at 12 weeks posttreatment was 99% (98/99) in patients with genotype 1 or 4 infection; 100% (5/5) in treatment-experienced cirrhotic patients with genotype 1 infection; 100% (10/10) in patients with genotype 2 infection; and 83% (5/6) in patients with genotype 3 infection. There were no treatment discontinuations due to adverse events (AEs). The most frequent non-bleeding AEs were fatigue, headache, diarrhoea, nausea and insomnia. Bleeding AEs occurred in 22 patients, of which all but one were considered unrelated to treatment. CONCLUSION: Treatment with ledipasvir-sofosbuvir for patients with HCV genotype 1 or 4 infection or sofosbuvir plus ribavirin for patients with genotype 2 or 3 infection was highly effective and well tolerated among those with inherited bleeding disorders.

All-oral direct-acting antiviral therapy in HCV-advanced liver disease is effective in real-world practice: observations through HCV-TARGET database.

BACKGROUND: Chronic hepatitis C virus therapy in patients with advanced liver disease remains a clinical challenge. HCV-TARGET collects data in patients treated at tertiary academic and community centres. AIM: To assess efficacy of all-oral HCV therapy in advanced liver disease. METHODS: Between December 2013 and October 2014, 240 patients with a MELD score of ≥10 initiated HCV treatment with an all-oral regimen. Data from the 220 patients who completed 12-week follow-up were analysed. RESULTS: Genotype 1 (GT1) patients had higher sustained virological response (SVR) when treated with sofosbuvir plus simeprevir ± ribavirin than with sofosbuvir plus ribavirin (66-74% vs. 54%); GT1b vs GT1a (84% vs. 64%). SVR for GT2 was 72% with sofosbuvir plus ribavirin, while GT3 patients had a substantially lower response (35%). A decrease in MELD score was not clearly related to SVR over the short course of follow-up although some had improvements in MELD score, serum bilirubin and albumin. A predictor of virological response was albumin level while negative predictors were elevated bilirubin level and GT1a. Most patients with GT1 were treated with approximately 12-week duration of sofosbuvir and simeprevir ± ribavirin therapy while GT2 and GT3 patients were treated with approximately 12 and 24 weeks of sofosbuvir plus ribavirin respectively. CONCLUSIONS: All-oral therapies are effective among patients with advanced liver disease with high levels of success in GT2 and GT1b, and may serve to reduce the severity of liver disease after SVR. Treatment for GT3 patients remains an unmet need. Clinical trial number: NCT01474811.

Treatment of severe recurrent hepatitis C after liver transplantation in HIV infected patients using sofosbuvir-based therapy.

BACKGROUND: For liver transplant recipients with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) co-infection, recurrence after LT is associated with a higher risk of graft loss than for HCV mono-infected patients. Prior HCV treatment options were limited by side effects and drug-drug interactions. AIM: To evaluate treatment outcomes with sofosbuvir (SOF)-based therapy among HIV/HCV coinfected liver transplant recipients. METHODS: Access to SOF and ribavirin (RBV) prior to regulatory approval was attained via an international compassionate access program for transplant recipients with a life expectancy of 1 year or less in the absence of HCV treatment. This report focuses on the short and longer term outcomes in HCV-HIV co-infected liver transplant recipients. RESULTS: Twenty patients were treated, nine with early severe recurrence and 11 with cirrhosis. Eleven patients received SOF and RBV, one SOF, RBV and Peg-interferon, three SOF, RBV and simeprevir and five SOF, RBV and daclatasvir. Of the 18 patients who completed treatment, 16 (89%) achieved sustained virological response 12 weeks after the end of treatment (SVR12). Liver function tests (including bilirubin and albumin) improved significantly over time. Nineteen serious adverse events occurred in eight (40%) patients, none of them related to SOF. Two patients died during treatment and another, 1 year after the end of therapy, due to progressive end-stage liver disease. Importantly, HIV suppression was not compromised. No significant drug-drug interactions were reported. CONCLUSIONS: Sofosbuvir-based regimens are safe, well-tolerated and provide high rates of SVR in HCV-HIV co-infected patients with severe recurrence after-liver transplant.

Frailty predicts waitlist mortality in liver transplant candidates.

We aimed to determine whether frailty, a validated geriatric construct of increased vulnerability to physiologic stressors, predicts mortality in liver transplant candidates. Consecutive adult outpatients listed for liver transplant with laboratory Model for End-Stage Liver Disease (MELD) ≥ 12 at a single center (97% recruitment rate) underwent four frailty assessments: Fried Frailty, Short Physical Performance Battery (SPPB), Activities of Daily Living (ADL) and Instrumental ADL (IADL) scales. Competing risks models associated frailty with waitlist mortality (death/delisting for being too sick for liver transplant). Two hundred ninety-four listed liver transplant patients with MELD ≥ 12, median age 60 years and MELD 15 were followed for 12 months. By Fried Frailty score ≥3, 17% were frail; 11/51 (22%) of the frail versus 25/243 (10%) of the not frail died/were delisted (p = 0.03). Each 1-unit increase in the Fried Frailty score was associated with a 45% (95% confidence interval, 4-202) increased risk of waitlist mortality adjusted for MELD. Similarly, the adjusted risk of waitlist mortality associated with each 1-unit decrease (i.e. increasing frailty) in the Short Physical Performance Battery (hazard ratio 1.19, 95% confidence interval 1.07-1.32). Frailty is prevalent in liver transplant candidates. It strongly predicts waitlist mortality, even after adjustment for liver disease severity demonstrating the applicability and importance of the frailty construct in this population.

Telaprevir or boceprevir triple therapy in patients with chronic hepatitis C and varying severity of cirrhosis.

BACKGROUND: Risks and benefits of protease inhibitor (PI) (telaprevir or boceprevir) triple therapy in hepatitis C virus (HCV)-infected patients with mildly decompensated cirrhosis, including those wait-listed for liver transplantation (LT), are incompletely known. AIM: To assess virological responses and safety of PI triple therapy in patients with mildly decompensated Child-Pugh (CP) CP ≥6 vs. compensated (CP = 5) cirrhosis. METHODS: Multicentre cohort of 160 adults with cirrhosis treated with peginterferon/ribavirin (peg-IFN/RBV) plus telaprevir (69%) or boceprevir (31%), comparing outcomes between those with CP = 5 and CP ≥6. RESULTS: Patients, 47% with CP ≥6 cirrhosis (CP range 6-10), received PI triple therapy for a targeted duration of 48 weeks. The cohort was median age 59 years, 32% female, 59% genotype 1a, 35% previous null/partial responders. Sustained virological response at 12 weeks (SVR12) was achieved by 35% of patients with CP ≥6 vs. 54% of those with CP = 5 (P = 0.02). CP = 5, achievement of rapid virological response and genotype 1b/other, independently predicted SVR12. Compared to those with CP = 5, patients with CP ≥6 had more peg-IFN dose reductions, eltrombopag use, transfusions and hospitalisations to manage adverse events (all P < 0.05). Overall, 67 (42%) discontinued treatment early. Nine wait-listed patients were treated for a median of 97 days (IQR 60-160) prior to liver transplantation and five achieved post-LT SVR. CONCLUSIONS: In the presence of mild decompensation (Child-Pugh ≥6), SVR12 rates with protease inhibitor triple therapy are significantly reduced and adverse events increased. Thus, treatment with protease inhibitor triple therapy, if judged as necessary, should be undertaken with close monitoring and awareness of the significant risks.

A comparison of measured and calculated free 25(OH) vitamin D levels in clinical populations.

OBJECTIVE: Our goal was to compare direct quantitation of circulating free 25-hydroxyvitamin D (25(OH)D)levels to calculated free 25(OH)D levels and their relationships to intact PTH (iPTH), a biomarker of 25(OH)D effect, in humans with a range of clinical conditions. PATIENTS AND METHODS: Serum samples and clinical data were collected from 155 people: 111 without cirrhosis or pregnancy (comparison group), 24 cirrhotic patients with albumin <2.9 g/dL, and 20 pregnant women (second and third trimester). Total 25(OH)D (LC/MS/MS), free 25(OH)D (immunoassay), vitamin D binding protein (DBP) (immunoassay), albumin, and iPTH (immunoassay) were measured. RESULTS: Total 25(OH)D, DBP, and albumin were lowest in patients with cirrhosis, but measured free 25(OH)D was highest in this group (P < .001). DBP was highest in pregnant women (P < .001), but measured free 25(OH)D did not differ from the comparison group. Calculated free 25(OH)D was positively correlated with measured free 25(OH)D (P < .0001) but explained only 13% of the variability with calculated values higher than measured. African Americans had lower DBP than other ethnic populations within all clinical groups (P < .03), and differences between measured and calculated free 25(OH)D were greatest in African Americans (P < .001). Measured free 25(OH)D was correlated with total 25(OH)D (P < .0001; r(2) = 0.51), but calculated free 25(OH)D was not. Similarly, both measured free 25(OH)D (P < .02) and total 25(OH)D (P < .05) were correlated with iPTH, but calculated free 25(OH)D was not. CONCLUSIONS: Calculated free 25(OH)D levels varied considerably from direct measurements of free 25(OH)D with discrepancies greatest in the data for African Americans. Differences in DBP binding affinity likely contributed to estimation errors between the races. Directly measured free 25(OH)D concentrations were related to iPTH, but calculated estimates were not. Current algorithms to calculate free 25(OH)D may not be accurate. Further evaluation of directly measured free 25(OH)D levels to determine its role in research and clinical management of patients is needed.

Variability in free 25(OH) vitamin D levels in clinical populations.

UNLABELLED: Our goal was to determine total and directly measured free 25-hydroxy vitamin D (25(OH)D) serum levels in humans with a range of 25(OH)D levels and clinical conditions associated with low and high vitamin D binding protein levels. Serum samples and clinical data were collected from 106 subjects: 62 without cirrhosis or pregnancy, 24 cirrhotic patients with albumin <2.9g/dL, and 20 pregnant women. Total 25(OH)D (LC/MS/MS) and "free" 25(OH)D (immunoassay) were measured. Total 25(OH)D was significantly lower in liver disease patients but free 25(OH)D concentrations were significantly higher in this group (p<.001). Neither total nor free 25(OH)D concentrations were significantly different in pregnant women vs. the comparator group. There were significant direct positive relationships between free 25(OH)D and total 25(OH)D concentrations for the entire dataset and for each group (p<.0001), however slopes of relationships differed in the cirrhotic group compared to pregnant women or the comparator group. In cirrhotics: y (free 25(OH)D)=2.52+0.29×X(total 25 (OH)D), r(2)=.51, p<.001; y=1.45+0.09×X; r(2)=.77, p<.0001 for pregnant women; and y=1.11+0.12×X; r(2)=.72, p<.0001 for the comparator group). CONCLUSIONS: directly measured free 25(OH)D serum concentrations and relationships between total and free 25(OH)D vary with clinical conditions, and may differ from those predicted by indirect estimation methods. This article is part of a Special Issue entitled 'Vitamin D Workshop'.

Hepatitis C virus therapy is associated with lower health care costs not only in noncirrhotic patients but also in patients with end-stage liver disease.

BACKGROUND: The effect of anti-viral treatment on downstream costs for hepatitis C virus (HCV)-infected patients is unknown. AIM: To evaluate follow-up costs in patients with chronic HCV, stratified by liver disease severity. METHODS: Using a US private insurance database, mean all-cause per-patient-per-month (PPPM) US (2010) medical costs were calculated for HCV-infected persons who did and did not receive anti-HCV treatment between January 2002 and August 2010. Analysis was stratified by liver disease severity [noncirrhotic disease (NCD), compensated cirrhosis (CC) or end-stage liver disease (ESLD)] defined by ICD-9 and CPT codes. RESULTS: A total of 33 309 patients were included (78% NCD, 7% CC and 15% ESLD); 4111 individuals (12%) received anti-HCV treatment during the 2-year baseline period. Mean PPPM follow-up health care costs were significantly lower among treated patients with NCD ($900 vs. $1378 in untreated patients, P < 0.001) and ESLD ($3634 vs. $5071, P < 0.001) groups but not in the CC group ($1404 vs. $1795, P < 0.071; t-test). In a multivariable model adjusted for demographic characteristics, comorbidities, index date and geographical region, incremental cost ratios for total health care costs differed significantly (P < 0.001) between treated and untreated patients in the NCD and ESLD groups but not in the CC group. From this model, mean PPPM total health care costs between treated and untreated patients were $885 and $1370 in the NCD, $1369 and $1802 in the CC, and $3547 and $5137 in the ESLD groups, respectively. CONCLUSIONS: Anti-HCV therapy was associated with lower follow-up US health care costs, and these savings were independent of baseline patient comorbidities and stage of disease.

Patient, center and geographic characteristics of nationally placed livers.

Once a liver offer has been refused locally and regionally, it is offered nationally. We characterized nationally (n = 1567) versus locally (n = 19 893) placed grafts from adult, nonfulminant, deceased donor liver transplants (LT) from 2/1/05 to 1/31/10. Donors of nationally versus locally placed livers differed by age (50 vs. 42 years), positive HCV antibody (11 vs. 2%) and death from stroke (51 vs. 42%) (p < 0.001 for all). Recipients of nationally versus locally placed livers differed by LT-MELD (20 vs. 24), rates of ascites (35 vs. 37%), encephalopathy (12 vs. 15%), hepatocellular (17 vs. 24%) and nonhepatocellular exceptions (6 vs. 11%) (p ≤ 0.03 for all). Six (5%) centers utilized 64% of the nationally placed grafts while 43 (38%) centers accepted zero during the 5-year period; all high volume centers used ≥1. Compared to local distribution, transplantation with a nationally placed liver was associated with a similar adjusted risk of graft (HR, 0.99; 95% CI, 0.86-1.14) and patient (HR, 0.98; 95% CI, 0.84-1.14; p = 0.77) survival. In conclusion, utilization of nationally placed livers is highly concentrated in very few centers, with no increased adjusted risk of graft loss. These findings provide the foundation for a more informed discussion about changing our current liver allocation and distribution policies.

Gender differences in liver donor quality are predictive of graft loss.

Some studies have found that donor-recipient gender mismatch predicts posttransplant outcomes but whether this is independent of donor quality is unknown. To evaluate the association between gender mismatch and graft loss, 11 508 females (F) and 16 714 males (M) who underwent liver transplant from March 1, 2002 to December 31, 2007 were studied. Of 11 donor characteristics, clinically relevant differences between F and M donors were median age (47 vs. 39 years), height (165 vs. 178 cm) and proportion dying of stroke (59 vs. 35%) (p < 0.001 for all). The donor risk index was significantly lower for F than M donors (1.3 vs. 1.6, p < 0.001). Recipients of gender-mismatched grafts had an 11% higher risk of graft loss (p < 0.001). Compared to M→M donor-recipient-matched transplants in univariable analysis, F→M mismatch was associated with a 17% increased risk of graft loss (95% CI = 1.11-1.24, p < 0.001), whereas M→F mismatch was not (HR = 1.02; 95% CI = 0.96-1.09; p = 0.46). However, adjustment for significant recipient and donor factors eliminated the association between F→M mismatch and graft loss (HR = 0.95; 95% CI = 0.89-1.02; p = 0.18). In conclusion, donor quality differs significantly between female and male donors-female donors are older, shorter and die more frequently of stroke-and gender differences in donor quality, rather than gender mismatch are predictive of graft loss.

Molecular characterization of intrahepatic and extrahepatic hepatitis B virus (HBV) reservoirs in patients on suppressive antiviral therapy.

The hepatitis B virus (HBV) replicates via an error-prone reverse transcriptase generating potential drug-resistant quasispecies. The degree of HBV variability in liver vs peripheral blood mononuclear cells (PBMC) in patients on long-term suppressive antivirals is unclear. We characterized HBV replication, drug resistance and molecular diversity in patients with plasma HBV DNA undetectable by clinical assays. Explant liver (n=9), PBMC (n=6) and plasma (n=7) from nine such patients undergoing liver transplantation were evaluated for HBV genomes by sensitive PCR/nucleic acid hybridization assay. Cases with HBV DNA in liver and PBMC were tested for covalently closed circular DNA (HBV cccDNA). HBV polymerase (P) amplicons were cloned, sequenced and both P and overlapping surface (S) gene sequences were analysed. HBV DNA was detected in 43% (3/7) of plasma, 100% (9/9) of liver and 83% (5/6) of PBMC samples. HBV cccDNA was detected in all liver and one PBMC sample. Four patients had a clinical diagnosis of resistance. HBV P gene sequencing revealed 100% wild type (wt) in plasma (2/2), 83% wt in PBMC (5/6) but livers of 3/9 (33%) contained wt and 6/9 (66%) carried resistance to lamivudine and/or adefovir. The translated S gene revealed no changes affecting HBV antigenicity. Sequences from livers with antiviral resistant mutants revealed greater interpatient quasispecies diversity. Despite apparent HBV suppression, the liver continues to support HBV replication and extrahepatic HBV can be detected. PBMC may be a sanctuary for wt virus during antiviral therapy, while the liver harbours more drug-resistant viruses. Drug resistance correlates with intrahepatic viral diversity.

Height contributes to the gender difference in wait-list mortality under the MELD-based liver allocation system.

This study examined factors associated with the gender disparity in wait-list mortality in the MELD era. Adult patients listed for liver transplantation from 2002 to 2008 were included. Females [12 585(36%)] and males [22 126(64%)] differed clinically by age (54 vs. 52 years), height (1.6 vs. 1.8 m), listing estimated glomerular filtration rate [(eGFR); 70 vs. 83 mL/min] and cirrhosis etiology. Holding MELD constant, females were at 19% (95% CI, 1.13-1.25, p < 0.001) higher risk of wait-list mortality than males under the current allocation system. The relative hazard increased with worsening renal function, whether measured by serum creatinine or eGFR. Adjustment for MELD, age, African-American race, cirrhosis etiology, region and ABO group attenuated this relative hazard (HR 1.16; 95% CI, 1.10-1.22; p < 0.001) but additional adjustment for height completely explained this gender disparity in wait-list mortality (HR 1.05; 95% CI, 0.98-1.12; p = 0.2). Transplantation rates, however, remained lower among females, even after adjustment for height (HR 0.88; 95% CI, 0.82-0.92; p < 0.001). In conclusion, under the current liver allocation system, women have a 19% increased risk of wait-list mortality compared to men with the same MELD scores. Height contributes to this gender disparity, possibly reflecting differences in transplantation rates for shorter individuals.

Virologic and clinical outcomes of hepatitis B virus infection in HIV-HBV coinfected transplant recipients.

Liver transplantation (LT) is the treatment of choice for end-stage liver disease, but is controversial in patients with human immunodeficiency virus (HIV) infection. Using a prospective cohort of HIV-hepatitis B virus (HBV) coinfected patients transplanted between 2001-2007; outcomes including survival and HBV clinical recurrence were determined. Twenty-two coinfected patients underwent LT; 45% had detectable HBV DNA pre-LT and 72% were receiving anti-HBV drugs with efficacy against lamivudine-resistant HBV. Post-LT, all patients received hepatitis B immune globulin (HBIG) plus nucleos(t)ide analogues and remained HBsAg negative without clinical evidence of HBV recurrence, with a median follow-up 3.5 years. Low-level HBV viremia (median 108 IU/mL, range 9-789) was intermittently detected in 7/13 but not associated with HBsAg detection or ALT elevation. Compared with 20 HBV monoinfected patients on similar HBV prophylaxis and median follow-up of 4.0 years, patient and graft survival were similar: 100% versus 85% in HBV mono- versus coinfected patients (p = 0.08, log rank test). LT is effective for HIV-HBV coinfected patients with complications of cirrhosis, including those who are HBV DNA positive at the time of LT. Combination HBIG and antivirals is effective as prophylaxis with no clinical evidence of HBV recurrence but low-level HBV DNA is detectable in approximately 50% of recipients.

Incidence and severity of acute cellular rejection in recipients undergoing adult living donor or deceased donor liver transplantation.

Living donor liver transplantation (LDLT) may have better immunological outcomes compared to deceased donor liver transplantation (DDLT). The aim of this study was to analyze the incidence of acute cellular rejection (ACR) after LDLT and DDLT. Data from the adult-to-adult living donor liver transplantation (A2ALL) retrospective cohort study on 593 liver transplants done between May 1998 and March 2004 were studied (380 LDLT; 213 DDLT). Median LDLT and DDLT follow-up was 778 and 713 days, respectively. Rates of clinically treated and biopsy-proven ACR were compared. There were 174 (46%) LDLT and 80 (38%) DDLT recipients with >/=1 clinically treated episodes of ACR, whereas 103 (27%) LDLT and 58 (27%) DDLT recipients had >/=1 biopsy-proven ACR episode. A higher proportion of LDLT recipients had clinically treated ACR (p = 0.052), but this difference was largely attributable to one center. There were similar proportions of biopsy-proven rejection (p = 0.97) and graft loss due to rejection (p = 0.16). Longer cold ischemia time was associated with a higher rate of ACR in both groups despite much shorter median cold ischemia time in LDLT. These data do not show an immunological advantage for LDLT, and therefore do not support the application of unique posttransplant immunosuppression protocols for LDLT recipients.

HIV-infected liver and kidney transplant recipients: 1- and 3-year outcomes.

Improvements in human immunodeficiency virus (HIV)-associated mortality make it difficult to deny transplantation based upon futility. Outcomes in the current management era are unknown. This is a prospective series of liver or kidney transplant recipients with stable HIV disease. Eleven liver and 18 kidney transplant recipients were followed for a median of 3.4 years (IQR [interquartile range] 2.9-4.9). One- and 3-year liver recipients' survival was 91% and 64%, respectively; kidney recipients' survival was 94%. One- and 3-year liver graft survival was 82% and 64%, respectively; kidney graft survival was 83%. Kidney patient and graft survival were similar to the general transplant population, while liver survival was similar to the older population, based on 1999-2004 transplants in the national database. CD4+ T-cell counts and HIV RNA levels were stable; and there were two opportunistic infections (OI). The 1- and 3-year cumulative incidence (95% confidence intervals [CI]) of rejection episodes for kidney recipients was 52% (28-75%) and 70% (48-92%), respectively. Two-thirds of hepatitis C virus (HCV)-infected patients, but no patient with hepatitis B virus (HBV) infection, recurred. Good transplant and HIV-related outcomes among kidney transplant recipients, and reasonable outcomes among liver recipients suggest that transplantation is an option for selected HIV-infected patients cared for at centers with adequate expertise.

Management of hepatitis C in liver transplant recipients.

Recurrent hepatitis C virus (HCV) disease is the leading cause of graft loss in liver transplant recipients with pre-transplant HCV infection. While natural history is variable, median time to recurrent cirrhosis is less than a decade. Factors contributing to risk of recurrence and rate of fibrosis progression are only partially known. Older donor age, treatment of acute rejection, cytomegalovirus infection and high pre-transplant viral load are most consistently linked with worse outcomes. Whether these factors can be modified to positively impact on HCV disease progression is unknown. The main therapeutic approach for patients with recurrent HCV disease has been the treatment with interferon and ribavirin (RBV) once recurrent disease is documented or progressive. Efficacy is lower than in nontransplant patients and tolerability, especially of RBV, is a major limitation. Stable or improved fibrosis scores are seen in the majority of sustained responders. Optimal dose, duration and timing of treatment have not been determined. Alternative strategies under study include pre-transplant treatment of decompensated cirrhotics, preemptive antiviral therapy started within weeks of transplantation and prophylactic therapy using HCV antibodies. Ongoing studies may establish a future role for alternative treatment approaches. Additionally, limited overall efficacy of interferon-based therapy in the transplant setting highlights the urgent need for new drug therapies.